Pavlovian fear conditioning is an important model both of human anxiety disorders and of learning. Extinction, the gradual reversal of fear conditioning, is similarly the explicit model for behavior therapy, one of the most effective treatments in psychiatry. Extinction of fear is also an important paradigm of active inhibitory learning that appears to depend on NMDA receptors in the amygdala. Despite its importance, the molecular and cellular substrates of extinction remain largely unstudied. The goal of this grant is to explore the molecular and physiological bases of the extinction of fear conditioning. I hypothesize that extinction may share many mechanisms with other forms of long-lasting learning and NMDA-receptor dependent synaptic plasticity. However, differences from other forms of learning will be especially informative, since they may suggest mechanisms specific to extinction. My preliminary studies have identified two such differences. First, massed training is more effective in generating extinction than is temporally distributed training. Our data suggest that extinction results from two opposing behavioral processes, a sensitizing effect of reminders, and a weakening effect of longer exposures to the conditional stimulus. We have also found that extinction, but not acquisition or expression, of conditional fear depends on L-type voltage-gated calcium channels (LVGCC). I now propose 1) To optimize protocols in mice to maximally isolate the weakening (extinction) or sensitization of fear conditioning following presentations of unreinforced conditioned stimuli; 2) To dissect these two processes using systemic and intracerebral drug administration; 3) To explore protocols that generate LVGCC-dependent synaptic changes in amygdala; and 4) To use drugs to correlate such LVGCC-LTP with behavioral extinction. In particular, the project will explore the roles of neurotransmitters and second messengers that have already been implicated in the generation extinction, including adrenergic and dopaminergic, cholinergic and GABAergic systems, and MAP kinase. My goal is an academic career in fundamental neuroscience research with potential for rapid translational application to psychiatric treatment. I plan to pursue this goal focusing on the study of extinction of fear conditioning as an important homologous model of psychiatric treatment, and to develop the pharmacological and physiological skills to maximize my ability to perform a molecular and cellular dissection of this phenomenon.